Jan Budczies, Daniel Kazdal, Michael Menzel, Susanne Beck, Klaus Kluck, Christian Altbürger, Constantin Schwab, Michael Allgäuer, Aysel Ahadova, Matthias Kloor, Peter Schirmacher, Solange Peters, Alwin Krämer, Petros Christopoulos, Albrecht Stenzinger
{"title":"Tumour mutational burden: clinical utility, challenges and emerging improvements","authors":"Jan Budczies, Daniel Kazdal, Michael Menzel, Susanne Beck, Klaus Kluck, Christian Altbürger, Constantin Schwab, Michael Allgäuer, Aysel Ahadova, Matthias Kloor, Peter Schirmacher, Solange Peters, Alwin Krämer, Petros Christopoulos, Albrecht Stenzinger","doi":"10.1038/s41571-024-00932-9","DOIUrl":null,"url":null,"abstract":"Tumour mutational burden (TMB), defined as the total number of somatic non-synonymous mutations present within the cancer genome, varies across and within cancer types. A first wave of retrospective and prospective research identified TMB as a predictive biomarker of response to immune-checkpoint inhibitors and culminated in the disease-agnostic approval of pembrolizumab for patients with TMB-high tumours based on data from the Keynote-158 trial. Although the applicability of outcomes from this trial to all cancer types and the optimal thresholds for TMB are yet to be ascertained, research into TMB is advancing along three principal avenues: enhancement of TMB assessments through rigorous quality control measures within the laboratory process, including the mitigation of confounding factors such as limited panel scope and low tumour purity; refinement of the traditional TMB framework through the incorporation of innovative concepts such as clonal, persistent or HLA-corrected TMB, tumour neoantigen load and mutational signatures; and integration of TMB with established and emerging biomarkers such as PD-L1 expression, microsatellite instability, immune gene expression profiles and the tumour immune contexture. Given its pivotal functions in both the pathogenesis of cancer and the ability of the immune system to recognize tumours, a profound comprehension of the foundational principles and the continued evolution of TMB are of paramount relevance for the field of oncology. Tumour mutational burden (TMB), reflecting the number of mutations present in the DNA of a tumour, is a biologically appealing biomarker of a response to immune-checkpoint inhibitors (ICIs). Nonetheless, the clinical predictive value of TMB for ICI response has thus far been mixed, with robust associations seen only for a few ICI-responsive cancer types. In this Review, the authors summarize the available data on TMB and discuss ongoing research efforts to improve the clinical utility of this biomarker.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":81.1000,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41571-024-00932-9.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Reviews Clinical Oncology","FirstCategoryId":"3","ListUrlMain":"https://www.nature.com/articles/s41571-024-00932-9","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Tumour mutational burden (TMB), defined as the total number of somatic non-synonymous mutations present within the cancer genome, varies across and within cancer types. A first wave of retrospective and prospective research identified TMB as a predictive biomarker of response to immune-checkpoint inhibitors and culminated in the disease-agnostic approval of pembrolizumab for patients with TMB-high tumours based on data from the Keynote-158 trial. Although the applicability of outcomes from this trial to all cancer types and the optimal thresholds for TMB are yet to be ascertained, research into TMB is advancing along three principal avenues: enhancement of TMB assessments through rigorous quality control measures within the laboratory process, including the mitigation of confounding factors such as limited panel scope and low tumour purity; refinement of the traditional TMB framework through the incorporation of innovative concepts such as clonal, persistent or HLA-corrected TMB, tumour neoantigen load and mutational signatures; and integration of TMB with established and emerging biomarkers such as PD-L1 expression, microsatellite instability, immune gene expression profiles and the tumour immune contexture. Given its pivotal functions in both the pathogenesis of cancer and the ability of the immune system to recognize tumours, a profound comprehension of the foundational principles and the continued evolution of TMB are of paramount relevance for the field of oncology. Tumour mutational burden (TMB), reflecting the number of mutations present in the DNA of a tumour, is a biologically appealing biomarker of a response to immune-checkpoint inhibitors (ICIs). Nonetheless, the clinical predictive value of TMB for ICI response has thus far been mixed, with robust associations seen only for a few ICI-responsive cancer types. In this Review, the authors summarize the available data on TMB and discuss ongoing research efforts to improve the clinical utility of this biomarker.
期刊介绍:
Nature Reviews publishes clinical content authored by internationally renowned clinical academics and researchers, catering to readers in the medical sciences at postgraduate levels and beyond. Although targeted at practicing doctors, researchers, and academics within specific specialties, the aim is to ensure accessibility for readers across various medical disciplines. The journal features in-depth Reviews offering authoritative and current information, contextualizing topics within the history and development of a field. Perspectives, News & Views articles, and the Research Highlights section provide topical discussions, opinions, and filtered primary research from diverse medical journals.